VLA-4 integrin modulates cellular responses to sorafenib in metastasis-related processes of B16F10 melanoma cells.

Metastatic progression in melanoma is driven by the coordinated activity of adhesion molecules and growth factor receptors, yet the functional interplay between integrins and VEGFR-related signaling remains poorly defined. This study investigated the role of α4β1 integrin, also known as very late antigen-4 (VLA-4), in modulating the response of B16F10 murine melanoma cells to sorafenib, a multikinase inhibitor with anti-VEGFR activity. Silencing of VLA-4 shifted the concentration-response profile to sorafenib, indicating increased cellular sensitivity to the drug. Functional assays revealed that VLA-4 differentially modulated the cellular responses induced by sorafenib: its knockdown potentiated the inhibitory effects of VEGFR blockade on adhesion to fibroblasts and clonogenicity, while attenuating the effects on extracellular matrix adhesion, migration, invasion, and AKT activation. Notably, ERK1/2 activation was not significantly affected. In endothelial-associated assays, including adhesion and transendothelial migration, the effects of sorafenib occurred independently of VLA-4 modulation. Sorafenib reduced AKT activation in non-silenced cells, whereas this effect was attenuated after VLA-4 knockdown, suggesting that VLA-4 expression influences the cellular response of the AKT pathway to sorafenib. Collectively, these findings suggest that VLA-4 modulates cellular responses to sorafenib in a context-dependent manner, supporting a functional association between integrin expression and the pharmacological responses observed in metastatic melanoma cells.